Substituted pyridones



.to the -hydroxy derivative.

Patented Sept. 26, 1950 SUBSTITUTED PYRIDONES Harry W. Coover,Rochester, N. Y., and Norman J. Bowman, Gary, Ind., assignors to Merck8; 00., Inc., Rahway, N. J., a corporation of New Jersey No Drawing.Original application July 11. 1945, Serial No. 604,536. Divided and thisapplication March 26, 1948, Serial No. 17,382

This invention relates to substituted 2-pyridones containing inparticular a substituent in the 5 position.

This application is a division of our co-pending application, Serial No.604,536, filed July 11, 1945, now Patent No. 2,481,573.

The condensation of 1,3-dicarbonyl compounds with cyanoacetamide andethyl cyanoacetate is Well known and leads in the former case to 4,6-

' substituted-3-cyano-Z-pyridones. 'The synthesis of certain importantbiologically active compounds utilizes condensations of this type. Thesynthesis of pyridoxin for example, involves as its first step thecondensation of alkoxy acetylacetone with cyanoacetamide to give6-methyl- 4-alkoxy-3-cyano 2 pyridone. Pyridoxin contains a hydroxylgroup in the 5-position and it is necessary to nitrate the condensationprodnot, reduce the nitro group to an amino group followed bydiazotization and hydrolysis.

We have discovered a new condensation which avoids these three steps. Wefound that it is possible to carry out the condensation withcyanoacetamide or ethyl cyanoacetate and a reagent substituted in such amanner that the resulting product, pyridone, will contain in the 5-position either the desired group or one which can be readily convertedinto such a group.

To achieve this desired result, we condense 1,3- dicarbonyl compoundscontaining a further substituent in the 2 position, with cyanoacetamideand ethylcyanoacetate. The condensation product then contains the'substituent originally in the 2 position of the 1,3-dicarbonyl compoundin the 5 position of the Z-pyridone.

X ON ROOCHX-GOR' CNCHQCONHQ R OH For example, 3-acetoxy-pentanedione-2,4condensed with cyanoacetamide gives 4,6-dimethyl- 5-acetoxy-2-pyridone.This is readily hydrolyzed Similar condensations can be carried out withethyl cyanoacetate instead of cyanoacetamide.

As 1,3-dicarbonyl compounds such derivatives as acetyl acetone, alkoxyacetylacetone, acetopyruvic esters and acetoacetic esters may bementioned. In the case of acetoacetic esters, the mechanism is differentin that ethyl alcohol is split out rather than water so that there willbe a hydroXyl group in the 4 position rather than an B group.

3 Claims. (Cl. 260-295) As required substituents in the 2 position ofthe above 1,3-dicarbonyl compounds such groups as halogen, hydroxyl,alkoxyl, acetoxy, cyano, alkyl, carboxyesters etc. may be used.

The 2-acetoxy-1,3-dicarbonyl compounds are readily prepared by theaction of potassium acetate and acetic acid under anhydrous conditionson 2-ch1oro-1,3-dicarbonyl compound. The chloro dicarbonyl compounds areprepared readily by, the action of sulfuryl chloride on the 1,3-dicarbonyl compound. This method has been used successfully on suchdifferent types as acetylacetone, methoxy-acetylacetone, acetoaceticesters and acetopyruvic esters. The yield of chloro compound is good inall cases, but with methoxy-acetylacetone and particularly withacetopyruvic esters, the yields of the acetoxy compound are much lowerthan in the other cases.

The hydroxylgroup in the 2 position of these condensation products canbe removed by converting to the chloro derivative using P015 in POCls,followed by catalytic hydrogenation which also.reduced the 3-c'yanogroup to an aminomethyl group. Through diazotization of this aminogroup, the hydroxy methyl derivative is obtained andthe 5-acetoxy groupalso converted to the E-hydroxy group. It can be seen that,

by the use of this synthesis, many interesting products, includingpyridoxin, alpha and beta pyricin can be prepared with improved yields.

A further advantage of the method of this invention is the fact that thesynthesis can be ac- .complished with fewer steps than those requiredvby conventional methods.

The following examples will serve to illustrate the invention, but it isunderstood that they in no way limit its scope.

Example 1 C10H10O3N2, 58. C, 4.85% H; found, 53.4

Treatment of this pyridone with P015 inPOCla or in chlorobenzene gives4,6-dimethyl-5-acetoxy-3-cyano-2-chloro pyridine M. P. 246'7withoxy-3-aminomethyl pyridine which was. not iso=- lated in pure statebut which was diazotizedand.

hydrolyzed to give the known compound 4,6-dimethyl--hydroXy-3-hydroxymethyl pyridine? isolated as thehydrochloride salt.

Example: 2

A condensation run under identical conditions. with 1-methoxy-3-acetoxy2,4 pentanedione, prepared from the 3-chloro derivative andcyanoacetamide gave 6-methyl 5 -acetoxy-4-metlnoxy-methyl-3-cyano-2-pyridone M. P. 2541-6: By the same steps ofchlorination, hydrogenation and diazotization the known compound pvt--ridoxin-4-methyl ether was prepared.

Examplafi.

A few drops of piperidine wereadded'to a solu:-

tion of 4.5 g: of '3-acetoxy-2;4-pentane'dione and.

3 g. of ethyl cyanoacetatein'ml. ofIw-arnr alcohol and the solution wasthen refluxed. fori one" hour; After standing for 24 hours;thezsolutiorr was concentrated and 25ml. of'concentratediam moniumhydroxide added. After standing for amide and: the resultingsolution.was placedin.

a sealed tube and heated to 150 'for 12. hours. The solutiomthencontained alarge precipitate. The solution was. made neutral to litmuswith concentrated HCl and a slight excess added... The alcohol was thenlargely evaporated off and. ml. of water added. The precipitateofZ-methyl- 3,4j6-trihydroxy-5-cyano pyridine .was filteredioff M'Z P.,330 dec. The acetoxy, group was hydrolyzedto the hydroxy group by theprolonged.

heating. in the sealed tube which afterv the condensationtookplacacontaihed sodium hydroxide in the alcohol.

Calc. for CvI-IsOsNz, 50.5% C, 3.6% 1-1:. found, 50.0 c; 13.95'H.

Example. 5..

To a solution of 8.1 g; of 3-chloro-2,4-pentanedione and 5 g. ofcyanoacetamide in 35 ml. of alcohol was added a few drops of piperidineand the solution refluxed for 12 hours. The solution. was thenevaporated nearly to dryness and cooled. The. solid precipitate wasfiltered from an small. amount ofioil and alcohol. Fractional solutionin a small amount of cold water left mainly the pyridone as aprecipitate and took the'cyanoacetamide into solution.Recrystallizationirom alcohol gave the product, 4,6-dimethyl- 5chloro-3-cyano-2-pyridone M. P. 279-. The

. structureof this compound was proven by a mixed melting point with thecompound prepared by the-.action of sulfuryl chloride on 4,6-dimethyl-3-cyano-Z-pyridone in benzene. This reaction proceeds rapidly and givesthe 5-chloropyridone.

We claim:

1*. 4,'6 dimethyl-B-acetoxy-3-cyano 2 chloropyridine.

2. 6-methyl-5-acetoxy--alkoxymethyl-B cyano-2-cliloropyridine.

3; A compound having the formula:

ornooo ON wherein.R.1 isselected from the group consisting of. methyl=-and. alkox-ymethyl.

1 H. W. COOVER.

NORMAN J. BOWMAN.

REFERENCES CITED The. followingreferences' are of record in the file ofthisspatent:

UNITED STATES PATENTS Number. Name Date "2 ,266,754 Harris Dec. 23, 1941Stiller -e Apr. 3, 1945 OTHER REFERENCES Harris: J. Amer. Chem. Soc.,vol. 61, Dec. 1939, pages 3307-3309

3. A COMPOUND HAVING THE FORMULA: